Opioids remain the most widely prescribed and abused class of medicines (2009 National Survey on Drug Use, 2009; Annual report, 2010). Addiction is not the only limiting factor for the effective use of these compounds as powerful painkillers, antitussives, antidepressants, or antipruritic agents. In addition to social and legal issues associated with their use for non-medical, recreational purposes, several adverse effects (e.g., dysphoria, constipation, respiratory depression, nausea, vomiting, etc.) (McCurdy et al., 2010) hinder their clinical usefulness and justify the enormous effort put forth by numerous investigators over the years to discover safer opioid therapeutics and/or non-addictive medications. Notwithstanding the continued development of many compounds with opioid activity, ranging from useful agents in the clinic to important chemical tools to study the endogenous opioid system, a safe, non-addictive and effective opioid drug is yet to be discovered (McCurdy et al., 2010).
Notable members of the superfamily of G protein-coupled receptors (GPCRs), mu-, delta-, and kappa-opioid (or MOP, DOP, and KOP) receptor subtypes (Evans et al., 1992; Kieffer et al., 1992; Minami et al., 1993; Chen et al., 1993) are natural targets for the majority of opioid ligands. The most clinically used opioid drugs act as agonists at the MOP receptor (McCurdy et al., 2010), and exert addiction liability through activity at this receptor (DeLander et al., 1984; Fields, 2007). Thus, it has been proposed that high-affinity selective ligands of the DOP and KOP receptors would provide more effective routes to discovering non-addictive analgesics (Nagase et al., 2011; Vanderah, 2010). In particular, KOP receptor agonists have been shown to be unable to activate the reward pathway (Wang et aL, 2010) while still acting as effective pain suppressors on the central nervous system (CNS) and/or the periphery (Vanderah, 2010), most likely through the Gi/o protein-mediated inhibition of cAMP production (Taussig et al., 1993), the blockade of calcium channels (Tallen, 1994), and/or the activation of the inward rectifier potassium channels (Henry et al., 1994). Unfortunately, the KOP receptor agonists developed to date are not ideal drugs as they exert side effects such as dysphoria (Land et al., 2009). However, KOP receptor-mediated dysphoric effects have recently been attributed to the activation of the p38 MAPK pathway following arrestin recruitment to the activated KOP receptor (Land et al., 2009; Bruchas et al., 2010; Chavkin, 2011). Therefore, KOP receptor-selective G-protein biased agonists, which do not recruit arrestin, have been proposed to be more effective analgesics, without the adverse effects triggered by the arrestin pathway (Chavkin, 2011). Such a functionally selective G protein-biased KOP receptor ligand (rives et al., 2012): 6′-guanidinonaltrindole (6′-GNTI) was reported. Although this morphine-derivative ligand is a promising lead compound for non-addictive analgesics acting at the KOP receptor with reduced liability for dysphoria, its effective use as a drug is severely limited by its physicochemical properties and its inability to cross the blood brain barrier.
The lack of a detailed molecular-level understanding of the interactions between opioids and their receptors has hindered successful receptor-based drug design. By revealing how opioid ligands bind to their receptors, recent high-resolution crystal structures of all 4 opioid receptor subtypes, i.e., the MOP (Manglik et al., 2012), DOP (Granier et al., 2012), KOP (Wu et al., 2012), and nociceptin/orphanin FQ (Thompson et al., 2012) receptors, offer an unprecedented opportunity to discover novel chemotypes targeting these proteins that might eventually be developed into more efficacious therapeutics (Filizola et al., 2012a; Filizola et al., 2012b).
Accordingly, there is a need for non-addictive analgesics and other therapeutics acting at the KOP receptor, especially ones that have reduced liability for dysphoria. The present invention is directed to meeting these and other needs.